PROJECT SUMMARY Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Current consensus is that the AD pathological process begins decades before clinical symptoms occur. This long ?preclinical? phase of AD can first be observable in middle- age as deposits of hyperphosphorylated tau (P-tau) in the transentorhinal cortex and subcortical nuclei such as the locus coeruleus (LC) and the nucleus basalis of Meynert. We have strong preliminary evidence showing that higher cerebrospinal fluid (CSF) levels of tau in cognitively normal older adults (mean age: 69.68.6 years) are associated with poorer REM sleep and sleep spindles characteristics, the same processes influenced by the LC. We also have broad evidence of lower NET uptake in the LC associated with stress and aging. Our study model poses that early onset of tauopathy in the LC results in chronic upregulation of LC activity. This would reflect on disruption of the two sleep phenomena dependent on LC silences (REM sleep and sleep spindles), also closely related to cognition and memory formation, as well as performance in task-attention tests. Further, we hypothesize that the now mostly accepted LC tracer [11C] MRB developed and extensively tested by our team, will show decreased uptake in the LC associated with CSF tau biomarkers and LC tonic and phasic dysfunction. We propose to test this hypothesis first by demonstrating that increases in CSF tau are associated in vivo with lower [11C]MRB PET uptake (Aim 1), and that lower [11C] MRB binding in the LC is associated with impaired REM sleep and sleep spindles characteristics (Aim 2), as well as lower measures of performance in task-related attention tests (Aim 3). To test these hypotheses, 30 older adults (age 60-75) balanced by sex, will first perform a full clinical evaluation and MRI (visits 1-2). Subjects will later undergo 7 days of actigraphy followed by nocturnal polysomnography (NPSG) (visit 3). A morning lumbar puncture (LP) will be performed after NPSG to obtain CSF, followed by attention tests. LC function will be analyzed by PET-MR using [11C] MRB, which will be performed 1-4 weeks after the LP (visit 4). There is the potential to identify: 1) an association between CSF tau and in vivo [11C] MRB uptake; 2) a mechanism by which tau pathology may contribute to sleep dysfunction; 3) evidence that LC dysfunction disrupts performance in attention tests; and, 4) LC dysfunction as a new therapeutic target for AD prevention.